This invention was supported in part by a grant or award from the United States Government, which has rights in the invention.
This invention relates to the administration of drugs across animal body surfaces. (As used herein, "drug" means any chemical substance other than an antibiotic useful for treating a medical disorder of an animal).
Certain drugs, e.g. insulin, which need to be administered frequently are not effectively absorbed when administered orally. For example, a number of problems are associated with conventional insulin therapy. Because of the necessity for and discomfort associated with frequent insulin injections, the patient's lifestyle is disrupted. Hence, many diabetics either refuse insulin therapy altogether or avoid intensive treatment regimes such as those which involve injections with each meal. In addition, certain patients, especially young children, elderly patients, and those who are blind and/or disabled, are precluded from insulin self-administration by injection. Furthermore, insulin absorption after subcutaneous injection is variable in terms of rate and amount depending upon factors such as exercise, local blood flow, depth and volume of injection, the presence of local proteases which degrade insulin, and perhaps other, unknown factors. Portable infusion pumps have now been employed to increase the ease of delivering subcutaneously meal-related insulin boluses. However, these devices are externally worn and therefore cumbersome, they require regular needle replacement, are expensive, and are not accepted by many patients. It is clear that a reproducible, reliable, and non-invasive means for delivering insulin would be highly desirable. What is needed especially is an insulin delivery system that would permit easy, rapid, and non-invasive administration of insulin at meal times, when blood glucose concentration rises to peak levels.
Since the discovery of insulin six decades ago, there have been many attempts to develop alternate means of insulin delivery. Insulin has been administered enterally, either alone or encapsulated in liposomes (microcapsules); sublingually; vaginally; reactally with or without surfactants; and as a nasal aerosol spray.
It is well known that certain small peptides can be absorbed through the nasal mucosa as a "snuff" or directly from aqueous solution without an adjuvant. Examples of peptides which can be administered by this route are vasopressin, adrenocorticotrophic hormone (ACTH), luteinizing hormone relasing hormone (LHRH), and oxytocin. Indeed, for patients with diabetes insipidus, the intranasal route is a standard means for vasopressin delivery. In contrast, in the absence of adjuvants, insulin, and many other drugs, are not absorbed across the nasal mucosa at physiological pH.
Several workers have attempted to mix insulin with adjuvants that might enhance nasal insulin absorption. Hirai et al. (Int. J. Pharmaceutics (1981) 9 165-184; Diabetes (1978) 27, 296-299; British Pat. No. 1,527,605; and U.S. Pat. No. 4,153,689; and Pontiroli et al. (1982) Br. Med J. 284, 303-386, have described the use of various bile salts to enhance absorption of insulin by the nasal mucosa.